Population divergence, including speciation and the origins of population structure, is the fundamental evolutionary process leading to the diversity of life. This research project will extend recent advances in a likelihood-based approach to divergence models. The new approach employs analytic integration over prior ditributions of model parameters within a Markov chain Monte Carlo framework. The method leads to a joint probability density function, proportional to the likelihood, that can be used for parameter estimation and log- likelihood ratio tests of nested demographic models. The new method will be adapted to general multi-population problems in divergence. Such problems have long been appreciated as requiring both a population genetic perspective and a phylogenetic perspective. The research plan outlines how these two can be brought together under a common MCMC simulation. This will be the first such method that does not assume a given phylogeny; that does not assume that gene flow has not occurred; and that makes no assumptions about the relative population sizes of sampled or ancestral populations. By providing estimates of the joint posterior density, proportional to the likelihood, the method will provide direct acces to log-likelihood ratio tests and to likelihood-based confidence intervals. The approach will also be extended to problems in sample identification and DNA barcoding. These new methods will be applied to a case study of divergence among species and subspecies of Chimpanzee. The methods will also be applied to large multi-population multi-locus data sets from human populations. PERFORMANCE SITE(S) (organization, city, state) Rutgers, the State University of New Jersy, New Brunswick New Jersey, USA The University of Copenhagen, Copenhagen, Denmark. PHS 398 (Rev. 04/06) Page 2 Form Page 2 Principal Investigator/Program Director (Last, First, Middle): Hey, Emanuel B. KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in the format shown below. Start with Principal Investigator(s). List all other key personnel in alphabetical order, last name first. Name eRA Commons User Name Organization Role on Project Hey, Emanuel B. EMANUELHEY Rutgers University PI Nielsen, Rasmus Univ. of Copenhagen Co-Pi OTHER SIGNIFICANT CONTRIBUTORS Name Organization Role on Project Human Embryonic Stem Cells [x] No Q yes If the proposed project Involves human embryonic stem cells, list below the registration number of the specific cell line(s) from the following list: http://stemcells.nih.qov/reqistrv/index.asp. Use continuation pages as needed. Ifaspecificlinecannotbereferencedatthistime,includeastatementthatonefromtheRegistrywillbeused. Cell Line PHS 398 (Rev. 04/06) Page 3 Form Page 2-continued Number the following pages consecutively throughout the application. Do not use suffixes such as 4a, 4b. Principal Investigator/Program Director (Last, First, Middle): Hey, Emanuel B The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page 1 Description, Performance Sites, Key Personnel, Other Significant Contributors, and Human Embryonic Stem Cells Table of Contents Detailed Budget for Initial Budget Period (or Modular Budget) Budget for Entire Proposed Period of Support (not applicable with Modular Budget) na Budgets Pertaining to Consortium/Contractual Arrangements (not applicable with Modular Budget) na Biographical Sketch - Principal Investigator/Program Director (Not to exceed four pages) Other Biographical Sketches (Not to exceed four pages for each - Seeinstructions) Resources 12 Research Plan, 13 Introduction to Revlsed/Resubmission Application (Not to exceed 3 pages.). 13 Introduction to Supplemental/Revision Application (Not to exceed one page.) na A. Specific Aims Jl B. Background and Significance 17 C. Preliminary Studies/Progress Report (Items A-D: not to exceed 25 pages). 22 D. Research Design and Methods 34 E. Human Subjects Research 41 Protection of Human Subjects (Required if Item 4 on the Face Page is marked Yes) na Data and Safety Monitoring Plan (Required if Item 4 on the Face Page is marked Yes and a Phase I, II, or III clinical trial is proposed) na Inclusion of Women and Minorities (Required if Item 4 on the Face Page is marked Yes and is Clinical Research) na Targeted/Planned Enrollment Table (for new and continuing clinical research studies) na Inclusion of Children (Required if Item 4 on the Face Page is marked Yes) na F. Vertebrate Animals na G. Select Agent Research na H. Literature Cited 41 I, Multiple PI Leadership Plan 46 J. Consortium/Contractual Arrangements 46 K. Resource Sharing na L. Letters of Support (e.g., Consultants) na Checklist. 47 Check if Appendix(Fivecollatedsets.NopagenumberingnecessaryforAppendix.) Appendix is Included Number of publications and manuscripts accepted for publication (not to exceed 10) Other items (list): PHS 398 (Rev. 04/06) Page 4 Form Page 3